Alteration of fexofenadine disposition in the rat isolated perfused liver following injection of bacterial lipopolysaccharide

Abstract

1The aim of the present study was to examine the effect of bacterial lipopolysaccharide (LPS) on the disposition of an organic anion transporting polypeptide and P-glycoprotein substrate in the rat isolated perfused liver.2Male Sprague-Dawley rats were divided into four groups. Three of the groups received 1, 2.5 or 5 mg/kg, i.p., Escherichia coli LPS in sterile saline. The fourth group received an equivalent volume of sterile saline i.p. Twenty-four hours after treatment, rats were anaesthetized and the liver isolated and perfused with fexofenadine at an initial concentration of 2000 ng/mL in a recirculating system. Perfusate and bile samples were collected for 60 min and the liver was collected at the end of the perfusion. Fexofenadine concentrations were determined by HPLC. Fexofenadine pharmacokinetic parameters, the final liver : perfusate (L : P) and bile : liver (B : L) concentration ratios were determined.3Injection of LPS changed the hepatic disposition of fexofenadine. The changes were most marked in the 5 mg/kg LPS group. Notably, clearance from the perfusate (CL) and into the bile (CLB; 5.9 ᠰ.6 and 1.24 ᠰ.20 mL/min, respectively), L : P (44 ᠱ1) and B : L (17 ᠲ) were all reduced (P < 0.05) in this group compared with control (CL 10.0 ᠱ.1 mL/min; CLB 2.7 ᠰ.5 mL/min; L : P 87 ᠱ4; and B : L 30 ᠴ).4In conclusion CL and CLB were reduced